1. Field of the Invention
This invention relates, in general, to a solid-phase support for high-throughput synthesis, and more particularly to substrates having particles attached thereto, the solid-phase support being capable of withstanding centrifugal forces generated during high-throughput synthesis.
2. Description of Related Art
Solid-phase synthesis of organic molecules is the method of choice for preparation of libraries and compound megaarrays, which are currently being applied for screening in the quest to find new drugs or pharmaceutical lead compounds, i.e., compounds which exhibit a particular biological activity of pharmaceutical interest. These leads can serve as a starting point for the selection and synthesis of a drug compound, which in addition to the particular biological activity of interest have pharmacologic and toxicologic properties suitable for administration to animals, including humans.
Solid-phase synthesis requires repetitions of several relatively simple operations of addition of reagents, incubation and separation of liquid-phases. In solid-phase synthesis, final compounds are synthesized attached to solid-phase supports that permit the use of mechanical means to separate intermediate, partially-synthesized compounds between synthesis steps. Various designs of manual and automated instruments for combinatorial synthesis utilizing solid-phase synthesis have appeared in patent and non-patent literature. For example, U.S. Pat. Nos. 5,202,418 and 5,338,831, both to Lebl et al., each describe a method of performing multiple synthesis of peptides on a solid carrier. U.S. Pat. No. 5,342,585, also to Lebl et al., describes an apparatus for multiple syntheses of peptides on solid support. U.S. Pat. No. 6,045,755, also to Lebl, et al., describes an apparatus and a method for combinatorial chemistry synthesis. The entire contents of the above patents are incorporated herein by this reference.
Some known instruments have employed centrifugation for the separation of solid and liquid-phases in order to provide devices that are capable of high-throughput synthesis. Such devices can utilize solid-phase particles, for example, macrobeads or microbeads, as a solid-phase support to which intermediate and final compounds are attached. Such solid-phase particles are generally suspended within a reaction vessel, which reaction vessel is subjected to centrifugal forces to separate the liquid and solid-phases. For example, U.S. Pat. No. 6,121,054 to Lebl, describes a method for separation of liquid and solid-phases for solid-phase organic synthesis in which a slurry of beads are suspended in a solvent. Similarly, U.S. Patent Application Publication No. US 2002/0044894 A1 to Lebl et al. describes an oligonucleotide synthesizer that utilizes centrifugation to separate the liquid-phase from beads. Generally, such instruments employ mechanical means to retain the solid-phase beads within a reaction vessel, for example, a well of a microtiter plate, during centrifugation. The entire contents of the above patent and publication are incorporated herein by this reference.
One means to retain the solid-phase beads is to tilt the reaction vessel to form pockets from which the solid-phase cannot be removed by centrifugal force. See, e.g., U.S. Pat. No. 6,121,054. Alternatively, mesh or other frit materials can be employed to enclose and restrain the beads within the reaction vessel. See, e.g., U.S. Patent Application Publication No. US 2002/0044894 A1. Disadvantageously, such retention means increase the mechanical complexity of the instruments and/or the reaction vessels.
What is needed is a solid-phase support for high-throughput synthesis that overcomes the above and other disadvantages of known instruments employing solid-phase particles suspended within reaction vessels.